CN117771249A - Lapattinib self-microemulsion composition and preparation method thereof - Google Patents

Abstract

The invention discloses a lapatinib self-microemulsion composition and a preparation method thereof, wherein the lapatinib self-microemulsion composition comprises, by weight, 0.1-15% of lapatinib, 5-50% of an oil phase, 10-80% of an emulsifying agent and 0-60% of a co-emulsifying agent. According to the invention, through screening oil phase, surfactant and cosurfactant with specific types and dosage proportions, the self-microemulsion composition can improve the solubility of lapatinib, greatly improve the in vivo membrane permeability of lapatinib, increase the penetrability of intestinal epithelial cells, further remarkably promote absorption and improve the bioavailability of medicines, and can reduce the dosage of lapatinib under the condition of keeping the same curative effect as an original ground tablet, further improve various adverse reactions and improve medication compliance.

Description

Lapattinib self-microemulsion composition and preparation method thereof

Technical Field

The invention relates to the technical field of lapatinib preparations, in particular to a lapatinib self-microemulsion composition and a preparation method thereof.

Background

Lapatinib (Lapatinib) is a tyrosine kinase inhibitor, and is sold under the trade nameTargeting therapy for breast cancer developed by the company glazin smith, uk, was approved by FDA for marketing at 13, 3, 2007, and was combined with cape The combination of the two groups of the three groups suitable for HER2 overexpression and has been previously treated in patients with advanced or metastatic breast cancer including anthracycline, taxane and trastuzumab therapies. Lapatinib can effectively inhibit HER-1 (ErbB 1) and HER-2 (ErbB 2) tyrosine kinase activities, and can be combined with intracellular HER2 receptor protein after entering cancer cells to block the activity of HER2 receptor, thereby inhibiting the growth and division of cancer cells.

Lapatinib is only available in the market at present in the form of tablets, and the tablet contains 250mg of Lapatinib in clinical preparation, and the daily oral dosage is 1250mg (5 tablets), but the bioavailability is less than 20%, and the high-dose medicine causes side effects, wherein gastrointestinal reactions are obvious, such as diarrhea, nausea and the like. The solubility of lapatinib has pH dependency, the solubility is increased under the acidic condition, the solubility is gradually reduced along with the increase of the pH, the lapatinib is almost insoluble (0.007 mg/mL) in water, the application of the lapatinib is limited by the low solubility of the lapatinib, and the medication compliance of patients is further reduced due to obvious gastrointestinal adverse reactions.

In addition, food has a certain effect on the absorption of lapatinib, and when taken together with food, the food can increase the exposure of the medicine in the body. C when lapatinib is administered with a low fat diet _max And AUC _0-∞ About 2.4 and 2.7 fold increase, respectively; c when lapatinib is administered with a high fat diet _max And AUC _0-∞ About 3-fold and 4.3-fold increase, respectively, with a significant difference between pre-meal and post-meal. Considering that the administration with meals may increase the exposure, in order to control the plasma concentration of lapatinib,the instructions state that the tablet must be taken on an empty stomach and at least two hours before and at least 1 hour after taking the dose, should not be taken.

The self-microemulsion drug delivery system is a uniform clear liquid formed by drugs, oil phase, surfactant and cosurfactant, and forms microemulsion spontaneously under gastrointestinal peristalsis after oral administration. The SMEDDS can improve the solubility of the medicine, promote the medicine to pass through a lymphatic transport way, and obviously improve the oral bioavailability of the insoluble medicine. After the self-microemulsion preparation forms the microemulsion in the gastrointestinal tract, the drug is wrapped in the tiny microemulsion and rapidly distributed in the whole gastrointestinal tract, the uniform particle size distribution of the microemulsion is beneficial to the absorption of the drug, and meanwhile, the self-microemulsion drug delivery system is beneficial to improving the fluidity of intestinal epithelial cell membranes, promoting the transmembrane transport of the drug, changing the connection between epithelial cells and promoting the alternative way transport of the drug; on the other hand, the self-microemulsion drug delivery system has a certain influence on the activities of an external pump and CYP450, stimulates the generation of lipoprotein and chylomicron, realizes lymphatic transport of the drug, and improves the absorption problem of insoluble drugs and the bioavailability of the drug by the series of mechanisms.

The patent application of application number CN201510196919.7 discloses pegylated lapatinib, and injection and preparation method thereof, wherein amino acid is used as a connecting bridge, the difficulty of direct coupling of polyethylene glycol and LPT is reduced, three types of reactions involved in the synthesis process (reaction of LPT and amino acid, reaction between amino acid and reaction of polyethylene glycol and Y) are expected to reduce toxicity and solve the problem of poor water solubility through pegylation of lapatinib, but the preparation process is more complex than self-microemulsion preparation, the cost is higher, a series of problems exist in the synthesis process, and the compliance of patients in administration is low compared with oral preparation.

The patent application of application number CN202011388653.3 discloses a self-microemulsion composition of tyrosine kinase inhibitors comprising: 0.1-40% tyrosine kinase inhibitor; 60-99.9% of carrier; the carrier comprises an oil phase, a surfactant and a cosurfactant, wherein the tyrosine kinase inhibitor comprises lapatinib, but no examples of lapatinib are disclosed in the specification, and whether the problems of improving the bioavailability and improving the difference between meals are not known.

In view of the high daily dose, low bioavailability, serious gastrointestinal adverse reactions and the like of lapatinib tablets, and the fact that only one tablet formulation is currently marketed, the clinical use of the tablet formulation has great limitation, and therefore, the development of new preparations is urgently needed.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a lapatinib self-microemulsion composition and a preparation method thereof. According to the invention, through screening oil phase, surfactant and cosurfactant in specific types and dosage proportions, the self-microemulsion composition can improve the solubility and bioavailability of lapatinib, and can reduce the dosage of lapatinib under the condition of keeping the same curative effect as the original ground tablet, thereby improving various adverse reactions and medication compliance.

In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:

according to a first embodiment of the present invention, there is provided a lapatinib self-microemulsion composition.

A self-microemulsion composition of lapatinib comprises lapatinib, an oil phase, an emulsifier and a coemulsifier.

Further, the lapatinib self-microemulsion composition comprises, by weight, 0.1-15% of lapatinib, 5-50% of an oil phase, 10-80% of an emulsifier and 0-60% of a co-emulsifier.

Further, the lapatinib self-microemulsion composition comprises, by weight, 0.1-10% of lapatinib, 5-50% of an oil phase, 10-80% of an emulsifier and 5-50% of a co-emulsifier.

Further, the mass percentage of the lapatinib is 0.1-10%, and the mass percentage of the lapatinib is 0.1%, 0.5%, 1%, 1.64%, 1.96%, 2%, 2.78%, 3%, 3.29%, 3.37%, 3.38%, 3.45%, 3.7%, 4%, 4.23%, 5.0%, 6%, 6.40%, 6.86%, 7%, 7.79%, 8%, 9% or 10%. Further, the lapatinib self-microemulsion composition comprises 1-5% by weight, preferably 2-4.5% by weight.

Further, the oil phase is 5-45% by mass, and the oil phase is 5%, 9.65%, 9.72%, 15%, 16.8%, 17%, 17.3%, 17.5%, 17.8%, 18%, 18.3%, 18.5%, 18.8%, 19%, 19.3%, 19.44%, 19.5%, 20%, 20.3%, 20.5%, 20.8%, 21%, 21.3%, 21.5%, 21.86%, 25%, 28.97%, 29.17%, 29.56%, 30%, 30.92%, 33.75%, 33.77%, 34.31%, 35%, 37.99%, 38.62%, 38.89%, 39.08%, 39.44%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 48% or 50% by mass. In the self-lapatinib self-microemulsion composition, when two auxiliary materials are respectively contained in an oil phase, the mass ratio of the two auxiliary materials is 1:9-9:1; the ratio of the two oil phases is: 1:1, 1:1.1, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1.1:1, 1.2:1, 1.5:1, 2:1, 3:1, 3.5:1, 4:1, 5:1, 5.2:1 or 5.5:1. Further, the weight percentage of the oil phase of the lapatinib self-microemulsion composition is 25-40%, preferably 25%, 28.97%, 29.17%, 29.56%, 30%, 30.92%, 33.75%, 33.77%, 34.31%, 35%, 37.99%, 38.62%, 38.89%, 39.08%, 39.44% and 40%.

Further, the mass percentage of the emulsifier is 15-80%, the mass percentage of the emulsifier is 15%, 19.31%, 20%, 21%, 21.63%, 22%, 22.48%, 22.64%, 23%, 24%, 24.51%, 24.64%, 25%, 25.97%, 26%, 27%, 28%, 28.89%, 28.97%, 29%, 29.41%, 30%, 31%, 31.25%, 32%, 33%, 34.03%, 34.48%, 35%, 36%, 37%, 38%, 38.62%, 38.63%, 38.89%, 39%, 40%, 41%, 42.25%, 43%, 43.45%, 43.72%, 43.75%, 44.07%, 44.28%, 45%, 45.10%, 46.05%, 46.34%, 46.67%, 47%, 48%, 49%, 50%, 50.69%, 51%, 52%, 53%, 54%, 55%, 56.72%, 56.78%, 60%, 65%, 69.52%, 70%, 75% or 80%. In the self-lapatinib self-microemulsion composition, when two auxiliary materials are respectively contained in the emulsifier, the mass ratio of the two auxiliary materials is 1:9-9:1; the ratio of the two emulsifiers is 1:1, 1:1.1, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1.1:1, 1.2:1, 1.5:1, 2:1, 3:1, 3.5:1, 4:1, 5:1, 5.2:1 or 5.5:1. Further, the weight percentage of the emulsifier in the lapatinib self-microemulsion composition is 15-35%, preferably 15%, 19.31%, 20%, 21%, 21.63%, 22%, 22.48%, 22.64%, 23%, 24%, 24.51%, 24.64%, 25%, 25.97%, 26%, 27%, 28%, 28.89%, 28.97%, 29%, 29.41%, 30%, 31%, 31.25%, 32%, 33%, 34.03%, 34.48%, 35%.

Further, the co-emulsifier is 10-50% by mass, and the co-emulsifier is 10%, 11.28%, 11.33%, 11.67%, 11.59%, 12.83%, 13.48%, 13.66%, 14.08%, 14.48%, 15%, 16.90%, 17.38%, 17.5%, 19.31%, 19.44%, 19.74%, 20%, 22.48%, 25%, 28.97%, 29.56%, 30%, 30.64%, 32.47%, 32.79%, 33.33%, 33.7%, 34.03%, 34.31%, 35%, 38.62%, 38.89%, 40%, 43.45%, 43.75%, 45%, 45.10%, 45.42% or 50% by mass. In the self-lapatinib self-microemulsion composition, when two auxiliary materials are respectively contained in the auxiliary emulsifier, the mass ratio of the two auxiliary materials is 1:9-9:1. Further, the weight percentage of the auxiliary emulsifier in the lapatinib self-microemulsion composition is 30-45%, preferably 30%, 30.64%, 32.47%, 32.79%, 33.33%, 33.7%, 34.03%, 34.31%, 35%, 38.62%, 38.89%, 40%, 43.45%, 43.75% and 45%.

Further, the oil phase is various pharmaceutically acceptable oil phases and is selected from one or more of natural vegetable oil, vegetable oil after structural modification and hydrolysis, or medium-chain-length fatty glyceride with the chain length of C8-C10.

Further, the oil phase is selected from: corn oil, sunflower oil (e.g., refined sunflower oil), sesame oil, peanut oil, soybean oil, safflower oil, olive oil, palm oil, cottonseed oil, coix seed oil, castor oil, hydrogenated castor oil, coconut oil C8/C10 mono-or diglycerides (Capmul MCM), coconut oil C8/C10 propylene glycol diester (Captex 200), coconut oil C8/C10 triglycerides (Captex 355), coconut aminopropyl betaine, purified acetylated monoglycerides (Miglyol 812), purified sunflower oil monoglycerides, polyethylene glycol laurates, mono-oleic acid glycerides, mono-linoleic acid glycerides, medium chain triglycerides, polyethylene glycol oleic acid glycerides, polyethylene glycol linoleic acid glycerides, polyethylene glycol caprylic acid capric acid glycerides, polyoxyethylene oleic acid glycerides, polyoxyethylene linoleic acid glycerides camellia acid glyceride, almond oil oleic acid PEG-6 glyceride, corn oil linoleic acid PEG-6 glyceride, oleic acid glyceride, egg yolk lecithin, soybean lecithin, dioleoyl lecithin, dilauroyl lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, cephalin, creatinine, inositol phosphatides, lysophosphatides, phosphatidic acid, phosphatidylglycerol, stearoyl/palmitoyl/oleoyl phosphatidylcholine, stearoyl/palmitoyl/oleoyl phosphatidylethanolamine, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol, distearoyl phosphatidylethanolamine, oleoyl phosphatidylcholine, caproic acid, caprylic acid, oleic acid, vitamin E, stearic acid, isopropyl laurate, isopropyl palmitate, isopropyl myristate (IPM), polyethylene glycol-6 oleate, medium chain glycerides, polyethylene glycol glyceryl linoleate, propylene glycol monolaurate (Capmul PG-12), propylene glycol monocapryol 90, sorbitol oleate, ethyl lunate, ethyl myristate, ethyl oleate, ethyl linoleate, tocopherols, glyceryl tricaprylate (Captex 8000), polyglycerol oleate (Plurol Oleique CC 497), oleoyl polyoxyethylene glycerides, and linoleoyl polyoxyethylene glycerides (Labrafil M2125 CS).

Further, the oil phase is selected from one or at least two of tricaprylin, caprylic capric acid mono-di glyceride, caprylic glyceride, propylene glycol mono-caprylate, caprylic capric acid mono-di triglyceride, isopropyl myristate, medium chain triglyceride, ethyl oleate, corn oil, oleic acid, monolinoleate, propylene glycol monolaurate, propylene glycol monocaprylate, caprylic capric polyethylene glycol glyceride, oleoyl polyoxyethylene glyceride, polyglycerol oleate, and linoleoyl polyoxyethylene glyceride.

Further, the oil phase is selected from the following combinations: the mixed oil phase of oleic acid and medium chain triglyceride, the mixed oil phase of oleic acid and monocaprylic acid glyceride, the mixed oil phase of oleic acid and oleoyl polyoxyethylene glyceride, the mixed oil phase of oleic acid and monocaprylic acid glyceride, the mixed oil phase of oleic acid and corn oil, the mixed oil phase of tricaprylic acid glyceride and propylene glycol monocaprylic acid glyceride, the mass ratio of the mixed oil phases is 1-9:1-9, and the ratio of the two oil phases is: 1:1, 1:1.1, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1.1:1, 1.2:1, 1.5:1, 2:1, 3:1, 3.5:1, 4:1, 5:1, 5.2:1 or 5.5:1.

Further, the emulsifier is selected from one or at least two of nonionic, anionic, cationic and zwitterionic surfactants.

Further, the method comprises the steps of, the emulsifier is selected from egg yolk lecithin, soybean lecithin, di-oleoyl lecithin, dilauroyl lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearyl lecithin, cephalin, creatinine, inositol phosphatide, lysophosphatide, phosphatidic acid, phosphatidylglycerol, stearoyl/palmitoyl/oleoyl phosphatidylcholine, stearoyl/palmitoyl/oleoyl phosphatidylethanolamine, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol, distearoyl phosphatidylethanolamine, oleoyl phosphatidylcholine, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, dimyristoyl phosphatidylserine, acetylated monoglyceride, phosphatidylethanolamine sorbitan fatty acid esters, polyethylene glycol glycerol amygdalinate, C8/C10 polyethylene glycol glycerides of coconut oil, polyoxyethylene lauryl stearate, polyethylene glycol 100 vitamin E succinate, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene castor oil (Cremophor EL 35), polyoxyethylene hydrogenated castor oil (Cremophor RH 40), polyoxyethylene polyoxypropylene copolymer (e.g., poloxamers 188 and 407), polyoxyethylene glycerides, polyoxyethylene sorbitan trioleate, polyoxyethylene glycerol trioleate, polyoxyethylene sorbitan fatty acid esters, sodium docusate, calcium docusate, potassium docusate, sodium lauryl sulfate, dipalmitoyl phosphatidic acid, ethoxylated castor oil, mannitol oleate polyoxyethylene ether, polyethylene glycol glycerides, polyoxyethylene glycol trioleate, oleoyl polyoxyethylene glyceride, polyethylene glycol fatty acid ester, polyethylene glycol-15 hydroxystearate (Solutol), polyethylene glycol-8-glycerocate caprylate/caprate, polyethylene glycol-32 glyceride laurate, polyethylene glycol glyceride caprylate, sorbitan sesquioleate, polysorbate (such as polysorbate 20, polysorbate 80), water-soluble natural vitamin E, span 80 (Span 80), tween80 (Tween 80), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), caprylic acid, sodium caprylate, bile acid and salts thereof, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-hexadecyl-N, N-dimethyl-3-ammonia (ammonio) -1-propane sulfonate, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g., 1-acyl-SN-glycerol-3-phosphate of ethanolamine, choline, serine, or threonine), N-alkyl-N, N-dimethylamino-1-propane sulfonate, 3-cholamide-1-propyldimethylamino-1-propane sulfonate, dodecyl phosphorylcholine, myristoyl lysophosphatidylcholine egg lysolecithin, polyglycerin fatty acid ester, propylene glycol monocaprylate, propylene glycol monolaurate, cetyl-trimethylammonium bromide, cetyl pyridinium chloride, polyethylene oxide/polypropylene oxide block copolymers (Pluronics/Tetronics, triton X-100, dodecyl beta-D-glucopyranoside), sodium taurinate, oleic acid, acyl carnitine, lysine, arginine, histidine, lysine, or at least two thereof.

Further, the emulsifier is selected from one or at least two of polyoxyethylated castor oil (Cremophor EL 35), polyoxyethylated hydrogenated castor oil (Cremophor RH 40, or RH 40), oleoyl polyoxyethylene glyceride, span 80, tween80, caprylic capric polyethylene glycol glyceride, propylene glycol monocaprylate, polyglyceryl fatty acid ester, lauroyl polyethylene glycol-32 glyceride, caprylic capric polyethylene glycol glyceride (Labrasol), oleoyl polyoxyethylene glyceride, polyethylene glycol glyceride, polysorbate (such as polysorbate 20, polysorbate 80), and propylene glycol monolaurate.

Further, the auxiliary emulsifier is selected from one or more of medium/short chain alcohol and ether.

Further, the co-emulsifier is selected from one or more of ethanol, propylene glycol, isopropanol, N-butanol, polyethylene glycol (molecular weight range of 100Da-10kDa,300Da-2000Da, or 400Da-1000 Da) such as polyethylene glycol 200-600 (such as PEG400, PEG 600), polyethylene glycol vitamin E succinate, propylene carbonate, tetrahydrofurfuryl alcohol, ethylene glycol furalcohol, glycerylfurfural, dimethyl isosorbide, dimethylacetamide, N-methylpyrrolidone, diethylene glycol monoethyl ether (Transcutol or Transcutol P or Transcutol HP or TP), ethylene glycol monoethyl ether, docosahexaenoic acid, cholesterol, azone, glycerol, ethyl acetate, polyethylene oxide, caprylic/capric polyethylene glycol glyceride, propylene carbonate, glyceryl monostearate, glyceryl distearate, polyglycerol-6-dioleate.

Further, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, caprylic/capric acid mono-di-triglyceride, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether.

Further, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, glyceryl monocaprylate, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether.

Further, the lapatinib self-microemulsion composition comprises lapatinib, oleoyl polyoxyethylene glyceride, oleic acid, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether.

Further, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, glycerol monolinoleate, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether.

Further, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, glycerol monooleate, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether.

Further, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether.

Further, the lapatinib self-microemulsion composition comprises lapatinib, medium chain triglyceride, oleic acid, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether.

Further, the lapatinib self-microemulsion composition comprises lapatinib, glyceryl tricaprylate, propylene glycol monocaprylate, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether.

Further, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil and PEG400.

Further, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil and PEG600.

Further, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, medium chain triglyceride, polyoxyethylene hydrogenated castor oil and PEG400.

Further, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, medium chain triglyceride, polyoxyethylene hydrogenated castor oil and PEG600.

Further, the self-microemulsion composition further comprises one or two of an antioxidant, a preservative and a sweetener; the antioxidant or preservative accounts for 0.005-0.5% of the total mass of the self-microemulsion composition; the sweetener accounts for 0.05-1% of the total mass of the self-microemulsion composition.

Further, the antioxidant is one or two selected from tert-butyl p-hydroxy anisole BHA, butyl hydroxy toluene BHT, vitamin C and vitamin E (dl-alpha-tocopherol).

Further, the sweetener is one or two selected from glucose, fructose, sucrose, maltose, starch sugar, stevioside, liquorice, disodium glycyrrhizinate, saccharin, sodium cyclamate, aspartame and lactose.

Further, the lapatinib forms and releases a microemulsion when the microemulsion composition is contacted with an aqueous medium, and the particle size of the microemulsion is 2-500 nm. Further, the lapatinib forms and releases a microemulsion from the microemulsion composition upon contact with an aqueous medium, the microemulsion having a particle size of less than 500nm, 450nm, 400nm, 350nm, 300nm, 250nm, 200nm, 150nm, 100nm, 95nm, 90nm, 85nm, 80nm, 75nm, 70nm, 65nm, 60nm, 55nm, 50nm, 45nm, 40nm, 35nm, 30nm, 25nm, 20nm, 15nm, 10nm or even less. Further, the lapatinib forms and releases a microemulsion from the microemulsion composition when the composition is contacted with an aqueous medium, and the particle size of the microemulsion is 50-500 nm or 10-300 nm or 10-250 nm or 10-200 nm or 10-150 nm or 10-60 nm or 10-100 nm or 10-50 nm.

In the invention, a preparation method of the self-microemulsion composition is provided, which comprises the following steps:

Evaluating the solubility of the carrier material oil phase, the emulsifier and the co-emulsifier for lapatinib; the self-microemulsion composition is prepared by dissolving lapatinib in a carrier substance with high solubility, adding the carrier substance with low solubility, and uniformly mixing.

Further, in the process of uniform mixing, lapatinib and a carrier substance with high solubility are uniformly mixed to obtain a mixed phase I; adding the carrier material with the second solubility into the first mixed phase, and uniformly mixing to obtain a second mixed phase; adding carrier material with low solubility into the mixed phase II, mixing, heating and stirring at 60-70deg.C for 10-30 min to obtain mixed phase III; adding the carrier material with the lowest solubility into the mixed phase III to obtain the final lapatinib self-microemulsion composition.

Further, the self-microemulsion composition of the present invention may use crystalline or amorphous, salt, anhydrate or hydrate, solvate, prodrug, metabolite, etc. of lapatinib.

According to a third embodiment of the present invention there is provided a lapatinib formulation comprising a self-microemulsion composition according to the present invention.

Further, the lapatinib formulation also includes a solid adsorbent.

Further, the solid adsorbent is selected from one or more of silicon dioxide, microcrystalline cellulose, corn starch, lactose, magnesium aluminum silicate, starch, micro powder silica gel, pregelatinized starch, polyvinylpyrrolidone K30, poloxamer, ethyl cellulose, polyethylene glycol (molecular weight 1000-20000, polyethylene glycol 4000, polyethylene glycol 6000), povidone (molecular weight 1000-360000), oxalic acid, lactose, mannitol, sorbitol, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyacrylic resin (E, RS, RL), hydroxypropyl methylcellulose, hydroxypropyl-beta-cyclodextrin, methylcellulose, chitin, carboxymethyl cellulose or dextran 80.

Further, the solid adsorbent is one or more selected from silicon dioxide, microcrystalline cellulose, magnesium aluminum silicate, micro silica gel and pregelatinized starch.

Further, the mass ratio of the self-microemulsion composition to the solid adsorbent is 0.5-2:1, preferably 1-1.5:1.

Further, the lapatinib preparation also comprises a flavoring agent, wherein the flavoring agent accounts for 0.05-0.5% of the total mass of the lapatinib preparation.

A lapatinib formulation, comprising a solid formulation and a liquid formulation. Wherein the solid preparation comprises one or more of tablets, capsules, granules, powder, dripping pills and films. The liquid formulation includes, but is not limited to, one or more of injection, soft capsule, ointment, suppository, aerosol.

Further, the solid preparation is prepared from the content and auxiliary materials through one or more steps of crushing, sieving, mixing, granulating and tabletting. The auxiliary materials are selected from one or more of filler, adsorbent, adhesive, lubricant, dispersant, disintegrating agent, wetting agent, perfume and pigment. The content is the self-microemulsion composition of the first embodiment.

The liquid preparation consists of contents and auxiliary agents. The auxiliary agent is one or more selected from preservative, stabilizer, antioxidant, aromatic, osmotic pressure regulator and flavoring agent. The content is the self-microemulsion composition of the first embodiment.

In the invention, the preparation method of the lapatinib preparation can be carried out by a person skilled in the art according to the preparation method of the conventional preparation in the art to obtain the corresponding preparation. For example: preparing a self-microemulsion composition containing lapatinib according to the method; sealing the self-microemulsion composition containing lapatinib in a soft capsule or a hard capsule; preferably, each capsule contains 0.5-1ml of the self-microemulsion composition containing lapatinib.

In the invention, the self-microemulsion composition containing lapatinib is mixed with water, biologically relevant media (such as SGF, SGF, fessiF and FassiF media) or gastrointestinal fluid, and O/W nanoemulsion with high clarity, uniform particle size and stable property and particle size of less than 250nm can be spontaneously formed; the contents can exist in a stable solution form when stored at room temperature; the self-microemulsion composition of the present invention is stable even under conditions of influence (e.g., 30.+ -. 2 ℃ C., 4 ℃ C., 10% by weight of water based on the composition is added, 15% by weight of water based on the composition is added).

In the invention, the self-microemulsion composition containing lapatinib is a solution system, and can spontaneously disperse to form O/W type nanoemulsion under gastrointestinal peristalsis when being taken orally, and has the advantages of high clarity, uniform particle size and stable property. The nanoemulsion has small particle size, can promote the dissolution of the medicine, increase the membrane permeability of abiraterone in vivo, increase the penetrability of intestinal epithelial cells, further obviously promote the absorption and obviously improve the bioavailability of the medicine. The self-microemulsion composition containing lapatinib can also remarkably reduce the influence of food on lapatinib absorption and reduce the difference between preprandial and postprandial, so that medicines can be taken under the conditions of empty stomach and satiety, and the limitation of taking time is reduced.

In the present invention, the self-microemulsion composition provided may be used as a carrier for hydrophobic, poorly absorbable or readily hydrolyzable drugs. The solubility of the lapatinib can be improved at room temperature, and the formed uniform and stable lapatinib-containing drug system can be spontaneously dispersed to form nanoemulsion after entering a body, so that the problem of absorption and transmembrane of the lapatinib in the body can be effectively solved. Through intensive research, the self-microemulsion composition containing lapatinib prepared by the invention has the advantages of greatly improved oral bioavailability and excellent stability in a humid or over-humid environment. Compared with microemulsion, the self-emulsifying solution has higher stability, can meet the requirement of long-term storage, and can be directly filled into packages such as soft capsules or hard capsules.

Compared with the prior art, the invention has the following beneficial technical effects:

1: the self-microemulsion composition loaded with lapatinib is prepared by selecting specific raw materials according to a specific proportion. The self-microemulsion composition has high solubility and high stability to lapatinib, and can spontaneously disperse to form O/W type nanoemulsion under gastrointestinal peristalsis, and has high clarity, uniform particle size and stable property; greatly improves the membrane permeability of lapatinib in vivo, increases the penetrability of intestinal epithelial cells, further remarkably promotes absorption and improves the bioavailability of the medicine.

2: the self-microemulsion composition containing lapatinib prepared by the invention can obviously reduce the influence of food on lapatinib absorption, and obviously reduce the difference between before meal and after meal, so that the self-microemulsion composition containing lapatinib can take medicines under the conditions of empty stomach and full stomach, and the limitation of taking time is reduced.

Detailed Description

The following examples illustrate the technical aspects of the invention, and the scope of the invention claimed includes but is not limited to the following examples.

Test 1: preparation of self-microemulsion composition:

according to the solubility of each component in the self-microemulsion system, dissolving lapatinib in a carrier component with high solubility in sequence from large to small, adding the next component after uniformly mixing the previous component, and finally obtaining clear and transparent yellow emulsion, namely the lapatinib self-microemulsion composition;

In the preparation process, if the added components are solid, the mixture is heated and stirred for 10 to 30 minutes at the temperature of between 60 and 70 ℃ to be dissolved until the reaction system is clear and transparent.

Optionally adding antioxidant or antiseptic during preparation.

Test 2: measurement test of microemulsion size:

lapattinib was diluted 100-fold with water from the microemulsion composition and measured by a nanosize analyzer. Each sample was tested at least three times to ensure accuracy of the results.

Test 3: solubility investigation

1g of auxiliary material is taken, excess lapatinib is added, and after sufficient ultrasound, the dissolved state is observed, and the result is shown in the following table 1:

remarks: peceol: glycerol monooleate; labrasol: caprylic capric polyethylene glycol glyceride; masine CC: glycerol monolinoleate; RH40: polyoxyethylene hydrogenated castor oil; MCT: medium chain triglycerides; EL35: polyoxyethylene castor oil; capmul MCM: caprylic capric acid mono-di-triglyceride; TP: diethylene glycol monoethyl ether; capmul MCM C8: glycerol monocaprylate; labrafil M1944CS: oleoyl polyoxyethylene glyceride

From the solubility study it is possible to obtain: lapatinib has better solubility in oleic acid, RH40, TP, PEG600 and PEG400, screens an oil phase, takes RH40 as a high-hydrophilicity surfactant, takes RH40 as a surfactant, has better emulsifying capacity than other surfactants, and takes TP, PEG600 and PEG400 as cosurfactants because the emulsifier is solid in normal temperature state and has toxicity easily caused by too high proportion of the emulsifier.

Test 4: compatibility test of auxiliary materials

According to the drug solubility test, selecting proper oil phase, surfactant and cosurfactant for investigation, firstly investigating the emulsification condition of the oil phase and the surfactant, and then carrying out subsequent blank milk screening. The results are shown in Table 2:

from the test results, it can be found that: oleic acid is mixed with corn oil and Medium Chain Triglyceride (MCT) in certain proportion, and the emulsification effect is better under the action of surfactant RH 4O. When the ratio of oleic acid to corn oil is changed to be (1.5:1), the particle size after emulsification becomes large and has a multimodal phenomenon, and the emulsification effect is basically consistent when the ratio of oleic acid to corn oil is (1:1.5), but the mixing ratio of oleic acid to corn oil is 1:1 is optimal in consideration of the problem of drug loading due to low solubility of lapatinib in corn oil.

Test 5: examination of blank milk

The oil phase is a mixed oil phase of oleic acid and MCT, the mass ratio of the oleic acid to the MCT is 1:1, the surfactant is RH40, the cosurfactant is TP, the proportion of the oil phase, the surfactant and the cosurfactant is examined, and the obtained particle size (nm) is shown in the following table 3:

the oil phase is the mixed oil phase of oleic acid and corn oil, the mass ratio of the oleic acid to the corn oil is 1:1, the surfactant is RH40, the cosurfactant is TP, the proportion of the oil phase, the surfactant and the cosurfactant is examined, and the obtained particle size (nm) is shown in the following table 4:

The oil phase is the mixed oil phase of oleic acid and corn oil, the mass ratio of the oleic acid to the corn oil is 1:1, the surfactant is RH40, the cosurfactant is PEG400, the proportion of the oil phase, the surfactant and the cosurfactant is examined, and the obtained particle size (nm) is shown in the following table 5:

the oil phase is the mixed oil phase of oleic acid and corn oil, the mass ratio of the oleic acid to the corn oil is 1:1, the surfactant is RH40, the cosurfactant is PEG600, the proportion of the oil phase, the surfactant and the cosurfactant is examined, and the obtained particle size (nm) is shown in the following table 6:

based on the screening of the blank milk, it was found that (oleic acid: corn oil 1:1): RH40: the emulsifying effect of the blank emulsion of TP is more ideal. To examine specific drug loading conditions, a part of drug loading example examination is carried out, and the method mainly comprises the following steps of (corn oil: oleic acid 1:1): RH40: TP, (oleic acid: MCT 1:1): RH40: TP is the optimal prescription, the proportion of each auxiliary material in the following prescription is also applicable to the oil phase: a mixed oil phase of (corn oil: oleic acid 1.5:1) and a mixed oil phase of (oleic acid: MCT 1.5:1).

Example 1

The prescription is as follows:

25mg of Lapattinib 3.45%, 140mg of corn oil 19.31%, 140mg of oleic acid 19.31%, 210mg of polyoxyethylene hydrogenated castor oil 28.97%, 210mg of diethylene glycol monoethyl ether 30%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 37.32nm.

Example 2

25mg of Lapattinib 3.45%, 140mg of corn oil 19.31%, 140mg of oleic acid 19.31%, 280mg of polyoxyethylene hydrogenated castor oil 38.62%, 140mg of diethylene glycol monoethyl ether 19.31%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 37.02nm.

Example 3

25mg of Lapattinib 3.45%, 140mg of corn oil 19.31%, 140mg of oleic acid 19.31%, 315mg of polyoxyethylene hydrogenated castor oil 43.45%, 105mg of diethylene glycol monoethyl ether 14.48%

The preparation process comprises the following steps: preparation procedure reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion was 36.25nm.

Example 4

25mg of Lapatinib 3.45%, 140mg of corn oil 19.31%, 140mg of oleic acid 19.31%, 321mg of polyoxyethylene hydrogenated castor oil 44.28%, 99mg of diethylene glycol monoethyl ether 13.66%

The preparation process comprises the following steps: preparation procedure reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion was 35.29nm.

Example 5

25mg of Lapattinib 3.45%, 140mg of corn oil 19.31%, 140mg of oleic acid 19.31%, 327mg of polyoxyethylene hydrogenated castor oil 45.1%, 93mg of diethylene glycol monoethyl ether 12.83%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 36.82nm.

Example 6

25mg of Lapattinib 3.45%, 140mg of corn oil 19.31%, 140mg of oleic acid 19.31%, 46.34% of polyoxyethylene hydrogenated castor oil 336mg, 84mg of diethylene glycol monoethyl ether 11.59%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 30.73nm.

Example 7

25mg of lapatinib 3.45%, 140mg of corn oil 19.31%, 140mg of oleic acid 19.31%, 280mg of polyoxyethylene hydrogenated castor oil 38.62%, 600 mg of polyethylene glycol 19.31%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 174.97nm.

Example 8

25mg of Lapattinib 3.45%, 105mg of medium chain triglyceride 14.48%, 105mg of oleic acid 14.48%, 367.5mg of polyoxyethylene hydrogenated castor oil 50.69%, 122.5mg of diethylene glycol monoethyl ether 16.90%

The preparation process comprises the following steps: preparation procedure reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion was 27.36nm.

Example 9

25mg of Lapattinib 3.45%, 105mg of medium chain triglyceride 14.48%, 105mg of oleic acid 14.48%, 163mg of polyoxyethylene hydrogenated castor oil 22.48%, 323 mg of diethylene glycol monoethyl ether 227 mg 45.10%

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 36.85nm.

Example 10

20mg of Lapattinib 2.78%, 105mg of medium-chain triglyceride 14.58%, 105mg of oleic acid 14.58%, 408.4mg of polyoxyethylene hydrogenated castor oil 59.72%, 600.6 mg of polyethylene glycol 11.33%

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 32.15nm.

Example 11

20mg of Lapattinib 2.78%, 105mg of medium-chain triglyceride 14.58%, 105mg of oleic acid 14.58%, 163mg of polyoxyethylene hydrogenated castor oil 22.64%, 600 mg of polyethylene glycol 227 mg and 45.42%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 332.84nm.

Example 12

20mg of lapatinib, 120mg of caprylic capric acid mono-di-triglyceride 11.76%, 230mg of oleic acid 22.55%, 150mg of polyoxyethylene hydrogenated castor oil 14.70%, 150mg of oleoyl polyoxyethylene glyceride 14.7% and 350mg of diethylene glycol monoethyl ether 34%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 103.78nm.

Example 13

25mg of Lapattinib 3.45%, 105mg of medium chain triglyceride 14.48%, 105mg of oleic acid 14.48%, 327mg of polyoxyethylene hydrogenated castor oil 45.1%, 163mg of diethylene glycol monoethyl ether 22.48%

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 90.55nm.

Example 14

20mg of Lapattinib 2.78%, 140mg of caprylic capric acid mono-di-triglyceride 19.44%, 280mg of polyoxyethylene hydrogenated castor oil 38.89%, 280mg of diethylene glycol monoethyl ether 38.89%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 151.83nm.

Example 15

15mg of lapatinib 1.64%, 200mg of glyceryl trioctanoate 21.86%, 400mg of polyoxyethylene hydrogenated castor oil 43.72%, 300mg of diethylene glycol monoethyl ether 32.79%

The preparation process comprises the following steps: the preparation process is referred to in test one.

Example 16

Lapatinib 80mg 10%, glyceryl tricaprylate 270mg 33.75%, polyoxyethylene hydrogenated castor oil 250mg 31.25%, PEG600 200mg 25% preparation process: the preparation process is referred to in test one.

Example 17

Lapatinib 65mg 6.4%, glyceryl caprylate 300mg 29.56%, polyoxyethylene hydrogenated castor oil 350mg 34.48%, PEG600 300mg 29.56%.

The preparation process comprises the following steps: the preparation process is referred to in test one.

Example 18

60mg of lapatinib, 25.97% of glyceryl trioctanoate, 60mg of propylene glycol monocaprylate, 7.79% of polyoxyethylene hydrogenated 40 castor oil, 200mg of polyoxyethylene hydrogenated 40 castor oil, 25.97% of diethylene glycol monoethyl ether, 250mg of diethylene glycol monoethyl ether and 32.47%.

The preparation process comprises the following steps: the preparation process is referred to in test one.

Example 19

Lapatinib 56mg 6.86%, caprylic capric acid mono-diglyceride 260mg 31.86%, oleoyl polyoxyethylene glyceride 50mg 6.13%, polyoxyethylene hydrogenated 40 castor oil 200mg 24.5%, diethylene glycol monoethyl ether 250mg 30.64%.

The preparation process comprises the following steps: the preparation process is referred to in test one.

Example 20

Lapatinib 30mg 4.23%, glycerol monooleate 140mg 19.72%, caprylic/capric polyethylene glycol glyceride 140mg 19.72%, tween80 300mg 42.25%, PEG400 100mg 14.08%.

The preparation process comprises the following steps: the preparation process is referred to in test one.

Example 21

Lapatinib 25mg 3.37%, glycerol monolinoleate 140mg 18.87%, oleoyl polyoxyethylene glyceride 150mg 20.22%, polyoxyethylene castor oil 327mg 44.07%, diethylene glycol monoethyl ether 100mg 13.48%.

The preparation process comprises the following steps: the preparation process is referred to in test one.

Example 22

20mg of lapatinib, 2.78% of caprylic capric acid mono-diglyceride 120mg, 16.67% of caprylic capric acid polyethylene glycol glyceride 160mg, 22.22% of caprylic capric acid polyethylene glycol glyceride, 46.67% of polyoxyethylene castor oil 336mg and 84mg of diethylene glycol monoethyl ether 11.67%.

The preparation process comprises the following steps: the preparation process is referred to in test one.

Example 23

25mg of lapatinib 3.45%, 150mg of corn oil 20.69%, 130mg of oleoyl polyoxyethylene glyceride 17.93%, 280mg of polyoxyethylene castor oil 38.62% and 140mg of glycerol 19.31%.

The preparation process comprises the following steps: the preparation process is referred to in test one.

Example 24

25mg of lapatinib, 110mg of ethyl oleate, 14.47% of medium chain glyceride 125mg, 16.45% of polyoxyethylene castor oil 350mg, 46.05% of diethylene glycol monoethyl ether 150mg and 19.74%.

The preparation process comprises the following steps: the preparation process is referred to in test one.

Example 25

25mg of Lapattinib 3.45%, 140mg of corn oil 19.31%, 140mg of oleic acid 19.31%, 140mg of polyoxyethylene hydrogenated castor oil 19.31%, 280mg of diethylene glycol monoethyl ether 38.62%

The preparation process comprises the following steps: preparation procedure reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion was 40.59nm.

Example 26

Lapatinib 25mg 3.45%, corn oil 35mg 4.82%, oleic acid 35mg 4.82%, polyoxyethylene hydrogenated castor oil 315mg 43.44%, diethylene glycol monoethyl ether 315mg 43.44%

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 17.78nm.

Example 27

25mg of Lapattinib 3.45%, 35mg of corn oil 4.82%, 35mg of oleic acid 4.82%, 504mg of polyoxyethylene hydrogenated castor oil 69.52%, 126mg of diethylene glycol monoethyl ether 17.38%

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 25.90nm.

Example 28

25mg of Lapattinib 3.45%, 35mg of MCT 4.83%, 35mg of oleic acid 4.83%, 315mg of polyoxyethylene hydrogenated castor oil 43.45%, 43.45% of diethylene glycol monoethyl ether 315mg

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 19.02nm.

Example 29

25mg of Lapattinib 3.45%, 35mg of MCT 4.83%, 35mg of oleic acid 4.83%, 504mg of polyoxyethylene hydrogenated castor oil 69.52%, 126mg of diethylene glycol monoethyl ether 17.38%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 36.14nm.

Example 30

20mg of Lapatinib 2.78%, 140mg of oleic acid 19.44%, 140mg of corn oil 19.44%, 46.67% of polyoxyethylene hydrogenated castor oil 336mg, and 11.67% of PEG600 84mg

The preparation process comprises the following steps: preparation procedure reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion was 63.26nm.

Example 31

20mg of Lapattinib 2.78%, 35mg of oleic acid 4.86%, 35mg of corn oil 4.86%, 315mg of polyoxyethylene hydrogenated castor oil 43.75%, 600 mg of PEG 43.75%

The preparation process comprises the following steps: preparation procedure reference experiment one, particle size test reference experiment two, the particle size of the obtained lapatinib nanoemulsion was 36.42nm.

Example 32

20mg of lapatinib 2.78%, 35mg of oleic acid 4.86%, 35mg of corn oil 4.86%, 504mg of polyoxyethylene hydrogenated castor oil 70%, 600 mg of PEG 126.17.5%

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 30.14nm.

Example 33

20mg of Lapatinib 2.78%, 140mg of oleic acid 19.44%, 140mg of corn oil 19.44%, 280mg of polyoxyethylene hydrogenated castor oil 38.89%, and 140mg of PEG400 19.44%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 114.40nm.

Example 34

20mg of Lapatinib 2.78%, 140mg of oleic acid 19.44%, 140mg of corn oil 19.44%, 46.67% of polyoxyethylene hydrogenated castor oil 336mg, and 11.67% of PEG400 84mg

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion was 50.36nm.

Example 35

20mg of Lapattinib 2.78%, 35mg of oleic acid 4.86%, 35mg of corn oil 4.86%, 315mg of polyoxyethylene hydrogenated castor oil 43.75%, 400 mg 43.75%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 21.54nm.

Example 36

20mg of lapatinib 2.78%, 35mg of oleic acid 4.86%, 35mg of corn oil 4.86%, 504mg of polyoxyethylene hydrogenated castor oil 70%, 400 mg of PEG 126mg 17.5%

The preparation process comprises the following steps: preparation procedure reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion was 29.78nm.

Example 37

20mg of Lapattinib 2.78%, 35mg of oleic acid 4.86%, 35mg of MCT 4.86%, 315mg of polyoxyethylene hydrogenated castor oil 43.75%, 600 mg 43.75%

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 26.15nm.

Example 38

20mg of lapatinib 2.78%, 35mg of oleic acid 4.86%, 35mg of MCT 4.86%, 504mg of polyoxyethylene hydrogenated castor oil 70%, 600 mg of PEG 126.17.5%

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 30.12nm.

Example 39

20mg of Lapattinib 2.78%, 105mg of oleic acid 14.58%, 105mg of MCT 14.58%, 245mg of polyoxyethylene hydrogenated castor oil 34.03%, 400 mg of PEG 34.03%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 212.84nm.

Example 40

20mg of Lapattinib 2.78%, 105mg of oleic acid 14.58%, 105mg of MCT 14.58%, 408.8mg of polyoxyethylene hydrogenated castor oil 56.78%, 400.2 mg of PEG 11.28%

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 35.13nm.

Example 41

20mg of Lapattinib 2.78%, 35mg of oleic acid 4.86%, 35mg of MCT 4.86%, 315mg of polyoxyethylene hydrogenated castor oil 43.75%, 400 mg 43.75%

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion was 21.28nm.

Example 42

20mg of Lapatinib 2.78%, 35mg of oleic acid 4.86%, 35mg of MCT 4.86%, 504mg of polyoxyethylene hydrogenated castor oil 70%, 400 mg of PEG 126mg 17.5%

The preparation process comprises the following steps: preparation procedure reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion was 29.59nm.

Example 43

25mg of Lapatinib 3.70%, 113.75mg of glyceryl tricaprylate 16.85%, 113.75mg of propylene glycol monocaprylate 16.85%, 195mg of polyoxyethylene hydrogenated castor oil 28.89%, 227.5mg of diethylene glycol monoethyl ether 33.7%.

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 31.89nm.

Example 44

Lapatinib 28mg 3.85%, glyceryl tricaprylate 122.5mg 16.82%, propylene glycol monocaprylate 122.5mg 16.82%, polyoxyethylene hydrogenated castor oil 157.5mg 21.63%, diethylene glycol monoethyl ether 297.5mg 40.87%.

The preparation process comprises the following steps: preparation procedure reference experiment one, particle size test reference experiment two, the particle size of the obtained lapatinib nanoemulsion was 46.14nm.

Example 45

28mg of lapatinib, 168mg of propylene glycol monocaprylate, 23.08 mg of glyceryl tricaprylate, 84mg of glyceryl tricaprylate, 11.54 mg of polyoxyethylene hydrogenated castor oil, 171.5mg of 23.56% and 276.5mg of diethylene glycol monoethyl ether, 37.98%.

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 89.3nm.

Example 46

Lapatinib 28mg 3.85%, propylene glycol monocaprylate 151.2mg 20.77%, trioctanoate 100.8mg 13.85%, polyoxyethylene hydrogenated castor oil 171.5mg 23.56%, diethylene glycol monoethyl ether 276.5mg 37.98%.

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion was 54.87nm.

Example 47

Lapatinib 28mg 3.85%, propylene glycol monocaprylate 126mg 17.3%, trioctanoate 126mg 17.3%, polyoxyethylene hydrogenated castor oil 224mg 30.77%, diethylene glycol monoethyl ether 224mg 30.77%.

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 30.99nm.

Example 48

Lapatinib 28mg 3.85%, propylene glycol monocaprylate 133mg 18.27%, glyceryl trioctanoate 133mg 18.27%, polyoxyethylene hydrogenated castor oil 217mg 29.81%, diethylene glycol monoethyl ether 217mg 29.81%.

The preparation process comprises the following steps: preparation procedure reference experiment one, particle size test reference experiment two, the particle size of the obtained lapatinib nanoemulsion was 33.69nm.

Example 49

Lapatinib 28mg 3.85%, propylene glycol monocaprylate 140mg 19.32%, glyceryl trioctanoate 140mg 19.32%, polyoxyethylene hydrogenated castor oil 210mg 28.85%, diethylene glycol monoethyl ether 210mg 28.85%.

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 38.4nm.

Example 50

Lapatinib 28mg 3.85%, propylene glycol monocaprylate 140mg 19.32%, glyceryl trioctanoate 140mg 19.32%, polyoxyethylene hydrogenated castor oil 186.9mg 25.67%, diethylene glycol monoethyl ether 233.1mg 32.02%.

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion was 54.88nm.

Example 51

Lapatinib 28mg 3.85%, propylene glycol monocaprylate 140mg 19.32%, glyceryl trioctanoate 140mg 19.32%, polyoxyethylene hydrogenated castor oil 175mg 24.04%, diethylene glycol monoethyl ether 245mg 33.65%.

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 68.99nm.

Example 52

28mg of Lapatinib 3.85%, 147mg of propylene glycol monocaprylate 20.19%, 147mg of glyceryl tricaprylate 20.19%, 224mg of polyoxyethylene hydrogenated castor oil 30.77%, 182mg of diethylene glycol monoethyl ether 25%.

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 36.47nm.

Example 53

Lapatinib 28mg 3.85%, propylene glycol monocaprylate 147mg 20.19%, trioctanoate 147mg 20.19%, polyoxyethylene hydrogenated castor oil 203mg 27.88%, diethylene glycol monoethyl ether 203mg 27.88%.

The preparation process comprises the following steps: preparation process reference test I and particle size test reference test II, and the particle size of the obtained lapatinib nanoemulsion is 77.52nm.

EXAMPLE 54 adsorbent inspection

The lapatinib nanoemulsion of example 1 was stirred and mixed with a solid adsorbent in a weight ratio, and the adsorption state of the obtained lapatinib preparation was examined. As shown in table 7:

note that: a: the adsorption effect is good, and the powder is dry and does not adhere to the wall. B: the adsorption effect is generally that part of the powdery particles adhere to the wall. C: poor adsorption effect and wall adhesion of a large amount of powdery particles. D: the adsorption effect is extremely poor, and part of oily liquid is not adsorbed.

As can be seen from the experimental results, the adsorption effect of the silicon dioxide is best, and the ratio of the silicon dioxide to the self-microemulsion can reach 1:1.5; the adsorption amount of the micro silica gel and the magnesium aluminum silicate is the next time.

Example 55

The lapatinib nanoemulsion of example 1 is prepared by using silicon dioxide, BHA and saccharin sodium as carriers, and can be further dried by the prior art such as a melting method, a solvent evaporation method, a freeze drying method or direct granulation. As shown in table 8:

example 56

Lapatinib 35mg 3.38%, oleic acid 200mg 19.32%, corn oil 200mg 19.32%, polyoxyethylene hydrogenated castor oil 255mg 24.64%, diethylene glycol monoethyl ether 345mg 33.33%.

The preparation process comprises the following steps: preparation process reference test one, particle size test reference test two, the particle size of the obtained lapatinib nanoemulsion is 36.08nm.

Example 57

25mg of Lapattinib 3.7%, 15.4% of oleic acid 104mg, 15.4% of corn oil 104mg, 196.4mg of polyoxyethylene hydrogenated castor oil 29.1% and 245.6mg of diethylene glycol monoethyl ether 36.39%

The preparation process comprises the following steps: preparation procedure reference experiment one, particle size test reference experiment two, the particle size of the obtained lapatinib nanoemulsion was 31.79nm.

Stability investigation

The lapatinib-containing compositions were obtained in the amount configuration of the above examples, while stability tests were performed on each lapatinib-containing composition: namely, the lapatinib-containing composition obtained in the example was left at room temperature (15 to 25 ℃) for 7d, at 4℃for 7d, and after 100-fold dilution with water, the stability of the lapatinib-containing composition was observed, and the results are shown in Table 9 below.

Table 9 investigation of stability of lapatinib-containing compositions

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The microemulsion compositions obtained in the examples were allowed to stand for a period of time without significant changes in content and without the formation of impurities, and the respective microemulsion compositions were stable.

Application example 1 pharmacokinetic study experiment on rats

The pharmacokinetic characteristics of the lapatinib self-microemulsion composition (test preparation T) or lapatinib tablet (reference preparation R) prepared by the invention are examined by single oral administration to rats under fasting conditions.

SD rats weighing 180-220g were randomly grouped.

The specific administration mode is as follows: in the reference group, rats were orally administered with a suspension (tablet) of lapatinib (reference formulation R) at a dose of 25mg/kg; the experimental group, rats, were orally administered the self-microemulsion composition prepared in the example (test formulation) at a dose of 25mg/kg.

After administration, the medicine is fasted for one night and 4 hours after stomach irrigation and administration, and water can be drunk at will.

Sampling design: 0.25h before and 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h after administration, 0.5mL venous blood was collected, and plasma was centrifuged.

The concentration of lapatinib in plasma was determined by LC-MS/MS method.

The pharmacokinetic parameter average results are shown in table 10 below:

as can be seen from the results in the table, at the same dose, the self-microemulsion composition prepared in the examples of the present invention, C _max And AUC _last Significantly improve the AUC of the prepared self-microemulsion composition _last About AUC of reference formulation (tablet) _last The relative bioavailability is improved by 3-13 times, and the peak time, the peak concentration and the absorption level variation degree of the drug among individuals are low when the bioavailability is improved.

Claims (10)

1. The self-microemulsion composition of lapatinib is characterized by comprising, by weight, 0.1-15% of lapatinib, 5-50% of an oil phase, 10-80% of an emulsifier and 0-60% of a co-emulsifier.

2. The lapatinib self-microemulsion composition according to claim 1, wherein said oil phase is a pharmaceutically acceptable variety of oil phases selected from one or more of natural vegetable oils, vegetable oils modified and hydrolyzed, or medium chain length fatty acid glycerides having a chain length between C8-C10;

the emulsifier is one or at least two selected from nonionic, anionic, cationic and zwitterionic surfactants;

the auxiliary emulsifier is one or more selected from medium/short chain alcohol and ether.

3. The lapatinib self-microemulsion composition according to claim 1, wherein said oil phase is selected from one or at least two of glyceryl tricaprylate, caprylic capric acid mono-di-glyceride, glyceryl caprylate, propylene glycol monocaprylate, caprylic capric acid mono-di-triglyceride, isopropyl myristate, medium chain triglycerides, ethyl oleate, corn oil, oleic acid, glyceryl monolinoleate, glyceryl monooleate, propylene glycol monolaurate, propylene glycol monocaprylate, caprylic capric polyethylene glycol glyceride, oleoyl polyoxyethylene glyceride, polyglyceryl oleate, linoleoyl polyoxyethylene glyceride;

The emulsifier is one or at least two selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, oleoyl polyoxyethylene glyceride, span 80, tween 80, caprylic capric acid polyethylene glycol glyceride, propylene glycol monocaprylate, polyglycerol fatty acid ester, lauroyl polyethylene glycol-32 glyceride, caprylic capric acid polyethylene glycol glyceride, oleoyl polyoxyethylene glyceride, polyethylene glycol glyceride, polysorbate and propylene glycol monolaurate;

the auxiliary emulsifier is selected from one or at least two of ethanol, propylene glycol, isopropanol, N-butanol, polyethylene glycol vitamin E succinate, propylene carbonate, tetrahydrofurfuryl alcohol, ethylene glycol furfuryl alcohol, glycerylfurfural, dimethyl isosorbide, dimethylacetamide, N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol monoethyl ether, docosahexaenoic acid, cholesterol, azone, glycerol, ethyl acetate, polyethylene oxide, caprylic capric polyethylene glycol glyceride, propylene carbonate, glycerin monostearate, glycerin distearate and polyglycerol-6-dioleate.

4. A lapatinib self-microemulsion composition according to claim 3, wherein said oil phase is selected from the group consisting of: the mixed oil phase of oleic acid and medium chain triglyceride, the mixed oil phase of oleic acid and monocaprylic acid glyceride, the mixed oil phase of oleic acid and oleoyl polyoxyethylene glyceride, the mixed oil phase of oleic acid and monoclinolic acid glyceride, the mixed oil phase of oleic acid and monocaprylic acid glyceride, the mixed oil phase of oleic acid and corn oil, and the mixed oil phase of tricaprylic acid glyceride and propylene glycol monocaprylic acid glyceride.

5. A lapatinib self-microemulsion composition according to claim 3, wherein said lapatinib self-microemulsion composition comprises lapatinib, oleic acid, caprylic capric acid mono-di-triglycerides, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether;

or, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, glyceryl monocaprylate, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether;

or, the lapatinib self-microemulsion composition comprises lapatinib, oleoyl polyoxyethylene glyceride, oleic acid, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether;

or, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, glyceryl monolinoleate, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether;

or, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, glycerol monooleate, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether;

or, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether;

or, the lapatinib self-microemulsion composition comprises lapatinib, medium chain triglyceride, oleic acid, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether;

Or, the lapatinib self-microemulsion composition comprises lapatinib, glyceryl tricaprylate, propylene glycol monocaprylate, polyoxyethylene hydrogenated castor oil and diethylene glycol monoethyl ether;

or, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil and PEG400;

or, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, corn oil, polyoxyethylene hydrogenated castor oil and PEG600;

or, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, medium chain triglyceride, polyoxyethylene hydrogenated castor oil and PEG400;

or, the lapatinib self-microemulsion composition comprises lapatinib, oleic acid, medium chain triglyceride, polyoxyethylene hydrogenated castor oil and PEG600.

6. The lapatinib self-microemulsion composition according to claim 1, wherein in said lapatinib self-microemulsion composition, when two excipients are contained in the oil phase respectively, the mass ratio of the two excipients is 1:9-9:1;

in the self-lapatinib self-microemulsion composition, when two auxiliary materials are respectively contained in the emulsifier, the mass ratio of the two auxiliary materials is 1:9-9:1.

7. The lapatinib self-microemulsion composition of claim 1, further comprising one or both of an antioxidant, a preservative, and a sweetener; the antioxidant or preservative accounts for 0.005-0.5% of the total mass of the self-microemulsion composition; the sweetener accounts for 0.05-1% of the total mass of the self-microemulsion composition.

8. A lapatinib formulation comprising the self-microemulsion composition of claim 1 and a solid adsorbent.

9. The lapatinib preparation according to claim 8, wherein the solid adsorbent is selected from one or more of silica, microcrystalline cellulose, corn starch, lactose, magnesium aluminum silicate, starch, micro powder silica gel, pregelatinized starch, polyvinylpyrrolidone K30, poloxamer, ethylcellulose, polyethylene glycol, povidone, oxalic acid, lactose, mannitol, sorbitol, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyacrylic resin, hydroxypropyl methylcellulose, hydroxypropyl- β -cyclodextrin, methylcellulose, chitin, carboxymethyl cellulose or dextran 80.

10. A method of preparing a self-microemulsion composition according to any one of claims 1 to 7, comprising the steps of:

Evaluating the solubility of the carrier material oil phase, the emulsifier and the co-emulsifier for lapatinib; firstly, dissolving lapatinib in a carrier substance with high solubility, and finally adding the carrier substance with low solubility, and uniformly mixing to obtain a self-microemulsion composition;

further, in the process of uniform mixing, lapatinib and a carrier substance with high solubility are uniformly mixed to obtain a mixed phase I; adding the carrier material with the second solubility into the first mixed phase, and uniformly mixing to obtain a second mixed phase; adding carrier material with low solubility into the mixed phase II, mixing, heating and stirring at 60-70deg.C for 10-30 min to obtain mixed phase III; adding the carrier material with the lowest solubility into the mixed phase III to obtain the lapatinib self-microemulsion composition.